Melatonin

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Melatonin

Description

Melatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule present in unicellular to vertebrate organisms. Melatonin is synthesized from tryptophan in the pinealocytes by the pineal gland and also is produced in other organs, tissues and fluids (extrapineal melatonin). Melatonin has lipophilic and hydrophilic nature which allows it to cross biological membranes. Therefore, melatonin is present in all subcellular compartments predominantly in the nucleus and mitochondria. Melatonin has pleiotropic functions with powerful antioxidant, anti-inflammatory and oncostatic effects with a wide spectrum of action particularly at the level of mitochondria. » MiPNet article

Abbreviation: aMT

Reference: Acuña-Castroviejo 2014 Cell Mol Life Sci

Melatonin and protection from mitochondrial damage

Publications in the MiPMap
Doerrier C (2015) Melatonin and attenuation of mitochondrial oxidative damage. Mitochondr Physiol Network 2015-03-03.

»

Doerrier C (2015) MiPNet

Abstract: Melatonin (aMT) is a potent antioxidant and anti-inflammatory molecule able to attenuate mitochondrial oxidative damage, preserving mitochondrial function and organization.


O2k-Network Lab: ES Granada Acuna-Castroviejo D, AT Innsbruck Gnaiger E

Pineal and extrapineal melatonin

Melatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule which is present in a broadrange of phylogenetic taxa, including bacteria, fungi, plants, algae, invertebrate and vertebrate organisms. Whereas pineal melatonin has been related with chronobiotic functions, extrapineal melatonin shows mainly antioxidant and antiinflammatory actions.

  1. Pineal melatonin: Pineal melatonin is synthesized from tryptophan in the pinealocytes by the pineal gland. Its production is controlled by a circadian signal from suprachiasmatic nucleus (SCN). At night photoreceptors of the retina generate a potential action which finally triggers an increment in the levels and activity of arylalkylamine N-acetyltransferase (AANAT) protein. AANAT is the penultimate enzyme in melatonin synthesis. However, during the day the light maintains these photoreceptors hyperpolarized, blocking melatonin synthesis. Therefore, melatonin presents maximum levels in plasma between 2-3 am, which are 10 times higher than diurnal levels. Once synthesized, melatonin is released into the bloodstream, accessing to cellular tissues and corporal fluids. Pineal melatonin is related to circadian functions.
  2. Extrapineal melatonin: Melatonin is produced in various tissues, fluids and organs other than the pineal gland. Extrapineal melatonin levels are in micromolar range and are thus much higher than the nanomolar pineal melatonin concentrations. The production of extrapineal melatonin is independent of the pineal synthesis and occurs in the tissues in a different functional context. Moreover, extrapineal melatonin differs from pineal melatonin in terms of its intracellular location and protection of the tissue.


Mechanisms of action

Two different mechanisms of action of melatonin have been described:

  1. Receptor-mediated mechanism: Melatonin binds to membrane receptors (such as MT1 and MT2), nuclear receptors (RZR/ROR) and cytosolic proteins (such calmodulin and calreticulin).
  2. Non receptor-mediated mechanism.

Due to its lipophilic and hydrophilic nature, melatonin can cross biological membranes. Therefore, melatonin is present in all subcellular compartments, predominantly in the nucleus and mitochondria. Melatonin exerts highly relevant functions at the level of mitochondria, which are the main target of melatonin. Mitochondria are an important source of reactive oxygen and nitrogen species (ROS/RNS) in the cell, and melatonin exerts important actions protecting against mitochondrial damage.


Main functions of extrapineal melatonin

Melatonin shows pleiotropic functions with a wide spectrum of properties.

Melatonin is a powerful antioxidant

  1. Melatonin presents direct free radical scavenging activity: Due to its structure and its high redox potential melatonin and its metabolites act as electron donors, scavenging ROS.
  2. Indirect antioxidant activity: Melatonin decreases ROS/RNS production, increases the expression and the activity of antioxidant systems (such as glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase).

Melatonin has anti-inflammatory properties

During inflammatory diseases (such as sepsis or fibromyalgia), an induction occurs in mitochondria of i-mtNOS (inducible mitochondrial isoform of nitric oxide synthase) which causes a significant rise in nitric oxide (NO●) production and consequently an increment in peroxinitrite anion (ONOO–) levels. Both NO● and ONOO– inhibit respiratory complexes, favoring electron leak and producing finally an oxidative-nitrosative stress able to damage cellular structures, resulting in mitochondrial failure and cell death. Melatonin inhibits iNOS (cytosolic isoform of nitric oxide synthase) and i-mtNOS expression, restoring NO● levels. Accordingly, melatonin decrease RNS and ROS production, maintaining an optimal mitochondrial function.

On the other hand, inflammatory processes result in the activation of the nuclear factor NF-kB which acts in the nucleus triggering the expression of several proinflammatory genes. Melatonin inhibits the activation of the NF-kB pathway.

Melatonin exhibits oncostatic effects

Melatonin inhibits cell proliferation or induces apoptosis activation of tumoral cells by different mechanisms of action.

The lipid composition of mitochondrial membranes is relevant to maintain an adequate fluidity and consequently the organization and function of mitochondria. Important phospholipids present in mitochondrial membranes are very susceptible to the ROS attack and to the damage by lipid peroxidation (LPO). Moreover, phospholipids such as cardiolipin (CL) are involved in CI and CIV activities, mitochondrial supramolecular organization in supercomplexes (SC), the integrity of mitochondrial network and apoptotic processes. Therefore, alterations in cardiolipin structure, content and/or acyl chains compositions have significant implications on mitochondrial function. Melatonin is able to protect these mitochondrial components against oxidative and nitrosative-related damage, providing and optimal membrane fluidity which is necessary for a proper mitochondrial function.

Conclusions

Mitochondrial dysfunction plays a key role in several pathologies such as neurodegenerative, cardiovascular and inflammatory diseases, metabolic disorders, ischemia-reperfusion, hypoxia, mucositis as well as in aging. Usually, mitochondrial dysfunction in these pathophysiological conditions is caused, at least in part, by an increment in oxidative and nitrosative stress. A large body of studies support that melatonin treatment protects against hyperoxidative damage mediated via various mechanisms. Melatonin allows an optimal mitochondrial function by their direct and indirect actions.

In summary, melatonin administration can counteract mitochondrial impairment mainly by decreasing ROS/RNS production, preventing LPO and hence reducing oxidative damage of relevant components of mitochondrial membranes such as cardiolipin and polyunsaturated fatty acid (PUFAs), allowing to maintain an adequate structure and function and consequently preserving bioenergetic processes.

References

  1. Ortiz F, Acuña-Castroviejo D, Doerrier C, Dayoub JC, López LC, Venegas C, García JA, López A, Volt H, Luna-Sánchez M, Escames G (2014) Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res 58:34-49. »PMID: 25388914
  2. Doerrier C, García JA, Volt H, Díaz-Casado ME, Lima-Cabello E, Ortiz F, Luna-Sánchez M, Escames G, López LC, Acuña-Castroviejo D (2014) Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry. Life Sci 121:158-65. »PMID: 25498899
  3. López A, García JA, Escames G, Venegas C, Ortiz F, López LC, Acuña-Castroviejo D (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 46:188-98. »PMID: 19054298
  4. Acuña-Castroviejo D, Carretero C, Doerrier C, López LC, García-Corzo L, Tresguerres JA, Escames G (2012) Melatonin protects lung mitochondria from aging. Age (Dordr)34:681-692. »PMID: 21614449
  5. Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC, Rosales-Corral S, Tan DX, Reiter RJ (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 71:2997-25. »PMID: 24554058
  6. Acuña-Castroviejo D, López LC, Escames G, López A, García JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221-240. »PMID: 21244359
  7. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR (2000) Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept 9:137-159. »PMID: 10899700

Melatonin and mitObesity

Work in progress by Gnaiger E 2020-02-10 linked to a preprint in preparation on BME and mitObesity.

References: Melatonin

 YearReferenceOrganismTissue;cell
Jiki 2018 Front Physiol2018Jiki Z, Lecour S, Nduhirabandi F (2018) Cardiovascular benefits of dietary melatonin: a myth or a reality?. Front Physiol 9:528.Human
Scarpelli 2018 J Pineal Res2018Scarpelli P, Almeida GT, Viçoso KL, Lima WR, Pereira LB, Meissner KA, Wrenger C, Rafaello A, Rizzuto R, Pozzan T, Garcia CRS (2018) Melatonin activate FIS1, DYN1 and DYN2 Plasmodium falciparum related-genes for mitochondria fission: mitoemerald-GFP as a tool to visualize mitochondria structure. J Pineal Res 66:e12484.
Kleszczynski 2018 Int J Mol Sci2018Kleszczyński K, Bilska B, Stegemann A, Flis DJ, Ziolkowski W, Pyza E, Luger TA, Reiter RJ, Böhm M, Slominski AT (2018) Melatonin and its metabolites ameliorate UVR-induced mitochondrial oxidative stress in human MNT-1 melanoma cells. Int J Mol Sci 19:E3786.MouseLiver
De Moura Alvorcem 2018 Mitochondrion2018De Moura Alvorcem L, Britto R, Parmeggiani B, Glanzel NM, Da Rosa-Junior NT, Cecatto C, Bobermin LD, Amaral AU, Wajner M, Leipnitz G (2018) Evidence that thiol group modification and reactive oxygen species are involved in hydrogen sulfide-induced mitochondrial permeability transition pore opening in rat cerebellum. Mitochondrion 47:141-50.RatNervous system
Da Silva 2017 Neurotox Res2017Da Silva JC, Amaral AU, Cecatto C, Wajner A, Dos Santos Godoy K, Ribeiro RT, de Mello Gonçalves A, Zanatta Â, da Rosa MS, Loureiro SO, Vargas CR, Leipnitz G, de Souza DOG, Wajner M (2017) α-Ketoadipic acid and α-aminoadipic acid cause disturbance of glutamatergic neurotransmission and induction of oxidative stress in vitro in brain of adolescent rats. Neurotox Res 32:276-90.RatNervous system
Lopez 2017 PLOS ONE2017López A, Ortiz F, Doerrier C, Venegas C, Fernández-Ortiz M, Aranda P, Díaz-Casado ME, Fernández-Gil B, Barriocanal-Casado E, Escames G, López L, Acuña-Castroviejo D (2017) Mitochondrial impairment and melatonin protection in parkinsonian mice do not depend of inducible or neuronal nitric oxide synthases. PLOS ONE 12:e0183090.Mouse
De Moura 2017 Neurotox Res2017de Moura Alvorcem L, da Rosa MS, Glänzel NM, Parmeggiani B, Grings M, Schmitz F, Wyse ATS, Wajner M, Leipnitz G (2017) Disruption of energy transfer and redox status by sulfite in hippocampus, striatum, and cerebellum of developing rats. Neurotox Res 32:264-75.RatNervous system
Maarman 2016 J Appl Physiol (1985)2016Maarman GJ, Andrew BM, Blackhurst DM, Ojuka EO (2016) Melatonin protects against uric acid-induced mitochondrial dysfunction, oxidative stress, and triglyceride accumulation in C2C12 myotubes. J Appl Physiol (1985) 122:1003-10.MouseSkeletal muscle
Doerrier 2016 Mitochondrion2016Doerrier C, García JA, Volt H, Díaz-Casado ME, Luna-Sánchez M, Fernández-Gil B, Escames G, López LC, Acuña-Castroviejo D (2016) Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network. Mitochondrion 27:56-63.MouseHeart
Volt 2016 J Pineal Res2016Volt H, García JA, Doerrier C, Díaz-Casado ME, Guerra-Librero A, López LC, Escames G, Tresguerres JA, Acuña-Castroviejo D (2016) Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res 60:193-205.MouseHeart
Garcia 2015 FASEB J2015García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J 29:3863-75.MouseHeart
Agil 2015 J Pineal Res2015Agil A, El-Hammadi M, Jiménez-Aranda A, Tassi M, Abdo W, Fernández-Vázquez G, Reiter RJ (2015) Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats. J Pineal Res 59:70-9.RatLiver
Ortiz 2015 J Pineal Res2015Ortiz F, Acuña-Castroviejo D, Doerrier C, Dayoub JC, López LC, Venegas C, García JA, López A, Volt H, Luna-Sánchez M, Escames G (2015) Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res 58:34-49.
Acuña-Castroviejo 2014 Cell Mol Life Sci2014Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC, Rosales-Corral S, Tan DX, Reiter RJ (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 71:2997-25.
Doerrier 2014 Life Sci2014Doerrier C, García JA, Volt H, Díaz-Casado ME, Lima-Cabello E, Ortiz F, Luna-Sánchez M, Escames G, López LC, Acuña-Castroviejo D (2014) Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry. Life Sci 121:158-65.MouseLiver
Jimenez-Aranda 2014 J Pineal Res2014Jimenéz-Aranda A, Fernández-Vázquez G, Serrano MM, Reiter RJ, Agil A (2014) Melatonin improves mitochondrial function in inguinal white adipose tissue of Zücker diabetic fatty rats. J Pineal Res 57:103-9.RatFat
Ortiz 2014 J Pineal Res2014Ortiz F, García JA, Acuña-Castroviejo D, Doerrier C, López A, Venegas C, Volt H, Luna-Sánchez M, López LC, Escames G (2014) The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS. J Pineal Res 56:71-81.
Rodriguez 2013 Int J Mol Sci2013Rodriguez C, Martín V, Herrera F, García-Santos G, Rodriguez-Blanco J, Casado-Zapico S, Sánchez-Sánchez AM, Suárez S, Puente-Moncada N, Anítua MJ, Antolín I (2013) Mechanisms Involved in the Pro-Apoptotic Effect of Melatonin in Cancer Cells. Int J Mol Sci 14:6597-613.
Sarti 2013 Int J Mol Sci2013Sarti P, Magnifico MC, Altieri F, Mastronicola D, Arese M (2013) New evidence for cross talk between melatonin and mitochondria mediated by a circadian-compatible interaction with nitric oxide. Int J Mol Sci 14:11259-76.HumanOther cell lines
Escames 2013 Horm Mol Biol Clin Investig2013Escames G, Diaz-Casado ME, Doerrier C, Luna-Sanchez M, Lopez LC, Acuna-Castroviejo D (2013) Early gender differences in the redox status of the brain mitochondria with age: effects of melatonin therapy. Horm Mol Biol Clin Investig 16(2):91-100.
Acuña-Castroviejo 2012 Age (Dordr)2012Acuña-Castroviejo D, Carretero M, Doerrier C, López LC, García-Corzo L, Tresguerres JA, Escames G (2012) Melatonin protects lung mitochondria from aging. Age (Dordr) 34(3):681-92.MouseLung;gill
Acuña-Castroviejo 2011 Curr Top Med Chem2011Acuña-Castroviejo D; López LC; Escames G; López A; García JA; Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221-240.
Hardeland 2009 Biofactors2009Hardeland R (2009) Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors 35:183-92.
Morota 2009 Exp Neurol2009Morota S, Månsson R, Hansson Magnus J, Kasuya K, Shimazu M, Hasegawa E, Yanagi S, Omi A, Uchino H, Elmér E (2009) Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders-specificity vs. toxicity. Exp Neurol 218:353-62.HumanLiver
Lopez 2009 J Pineal Res2009López A, García JA, Escames G, Venegas C, Ortiz F, López LC, Acuña-Castroviejo D (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 46:188-98.MouseLiver
Bromme 2008 J Pineal Res2008Brömme HJ, Peschke E, Israel G (2008) Photo-degradation of melatonin: influence of argon, hydrogenperoxide, and ethanol. J Pineal Res 44:366-72.
Reiter 2003 Acta Biochim Pol2003Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50:1129-46.
Bromme 2000 J Pineal Res2000Brömme HJ, Mörke W, Peschke E, Ebelt H, Peschke D (2000) Scavenging effect of melatonin on hydroxyl radicals generated by alloxan. J Pineal Res 44:366-72.
Tan 2000 Biol Signals Recept2000Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR (2000) Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept 9:137-59.
 YearReferenceOrganismTissue;cell
Ortiz 2013 Abstract SEOR2013Molecular Basis of the radiotherapy-induced mucositis, beneficial effects of melatonin.Rat
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MitoPedia: mitObesity drugs

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TermAbbreviationDescription
CurcuminCurcumin has been shown to possess significant anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anti-coagulant and anti-infective effects. The protective effects of curcumin on rat heart mitochondrial injuries induced by in vitro anoxia–reoxygenation were evaluated by Xu et al 2013. It was found that curcumin added before anoxia or immediately prior to reoxygenation exhibited remarkable protective effects against anoxia–reoxygenation induced oxidative damage to mitochondria.
ElamipretideBendaviaBendavia (Elamipretide) was developed as a mitochondria-targeted drug against degenerative diseases, including cardiac ischemia-reperfusion injury. Clinical trials showed variable results. It is a cationic tetrapeptide which readily passes cell membranes, associates with cardiolipin in the mitochondrial inner membrane. Supercomplex-associated CIV activity significantly improved in response to elamipretide treatment in the failing human heart.
FlavonoidsFlavonoids are a group of bioactive polyphenols with potential antioxidant and anti-inflammatory effects, abundant in fruits and vegetables, and in some medicinal herbs. Flavonoids are synthesized in plants from phenylalanine. Dietary intake of flavonoids as nutraceuticals is discussed for targeting T2D and other degenerative diseases.
MelatoninaMTMelatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule present in unicellular to vertebrate organisms. Melatonin is synthesized from tryptophan in the pinealocytes by the pineal gland and also is produced in other organs, tissues and fluids (extrapineal melatonin). Melatonin has lipophilic and hydrophilic nature which allows it to cross biological membranes. Therefore, melatonin is present in all subcellular compartments predominantly in the nucleus and mitochondria. Melatonin has pleiotropic functions with powerful antioxidant, anti-inflammatory and oncostatic effects with a wide spectrum of action particularly at the level of mitochondria. » MiPNet article
MetforminMetformin is mainly known as an important antidiabetic drug which is effective, however, in a wide spectrum of degenerative diseases. It is an inhibitor of Complex I.
RapamycinRapamycin is an inhibitor of the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). Rapamycin induces autophagy and dyscouples mitochondrial respiration. Rapamycin delays senescence in human cells, and extends lifespan in mice without detrimental effects on mitochondrial fitness in skeletal muscle.
ResveratrolResveratrol is a natural bioactive phenol prouced by several plants with antioxidant and anti-inflammatory effects. Dietary intake as nutraceutical is discussed for targeting mitochondria with a wide spectrum of action in degenerative diseases.
SpermidineSpermidine is a polycationic bioactive polyamine mainly found in wheat germ, soybean and various vegetables, involved in the regulation of mitophagy, cell growth and cell death. Like other caloric restriction mimetics, spermidine is effective in cardioprotection, neuroprotection and anticancer immunosuppression by preserving mitochondrial function and control of autophagy.
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